2.1.8 Smallpox

Grading & Level of Importance: C






Smallpox is a human disease without animal reservoirs.


According to the 1980 declaration of the World Health Organization (WHO), smallpox has been eradicated, mainly due to effective immunization (Edward Jenner, 18th century).


Major endemic areas were the Indian subcontinent and parts of Africa.


Smallpox is a member of the viral family poxvirus, genus orthopoxvirus, and species variola virus.


Highly contagious pustular disease caused by Poxvirus variola. Overlap with monkey pox and cowpox/catpox.

Aetiology & Pathogenesis

The DNA-Virus Poxvirus variolae is the largest (300 nm to 350 nm long ) of the human viral pathogens and has a brick-shaped appearance on electron microscopy. The virus is highly contagious and spreads through direct contact, by droplets, contaminated fomites, or airborne over long distances. The virus enters through the oro- or nasopharynx and replicates in the regional lymph nodes. On day 3 to 4 viremia with further dissemination to the bone marrow, spleen, and additional lymph node chains occurs, followed by a secondary viremia between day 8 to 12 after infection and the start of fever and severe illness. At this stage the virus becomes localized in small blood vessels of the dermis, resulting in the appearance  of rash.

Signs & Symptoms

The clinical course is severe. It begins with a non-specific febrile prodrome of general malaise, high fever, chills, vomiting, abdominal pain, headache. 1-3 days later, skin lesions appear, first at the forearms or face, scalp, palms and soles. Spread to the rest of the body with sparing of axillae and groins.


The lesions appear and mature simultaneously; in contrast to chicken pox, which present with lesions in different phases of development. Sequentially  umbilicated papules, vesicles, pustules, crusts, finally leaving typical umbilicated “varioliform” scars with eschars, appear.


Marked involvement of face, scalp, palms, and soles with sparing of axillae and groins. In contrast in chickenpox palms and soles are not involved.



  • Orthopoxviruses

    • Smallpox

    • Vaccinia

    • Cowpox

    • Monkey pox

  • Parapoxviruses

    • Ecthyma contagiosum (orf)

    • Milker’s nodule

  • Molluscum Contagiosum

Laboratory & other workups

The relatively large virus can be identified by electron microscopy, by special culture or by PCR.


  • Prominent reticular degeneration and necrosis of the epidermis,
  • Ballooning, and necrosis of keratinocytes
  • Intracytoplasmic globular deposits of virus capsid
  • Blister formation may be minimal. Multinucleated giant cells usually are absent

Accompanying papillary edema with erythrocyte extravasation and inflammatory infiltrate.


Severe disease starting with general symptoms (fever, malaise). Skin lesions appear 3 days after infection, followed by generalized symptoms due to viremia.


Bacterial superinfection.


Typical clinical picture and course; electronmicroscopy, PCR.

Differential diagnosis

Chickenpox, eczema herpeticum, disseminated zoster, hand-foot-mouth disease, drug eruptions, Stevens-Johnson syndrome, toxic epidermal necrolysis, generalized vaccinia, cowpox, monkeypox.

Prevention & Therapy

In the pre-eradication era, supportive care was the primary treatment available.


Tecovirimat was the first antiviral medicament for treatment of smallpox.


Finally, vaccination has been successful in the eradication of smallpox globally.


In 1798, Edward Jenner could demonstrate that cowpox protected against smallpox infection. By 1900 vaccinia virus, which is more closely related to horsepox, was globally used for vaccination. Today improved technology to develop tissue-culture-based live vaccines, live attenuated virus vaccines, and viral subunit vaccine products may be used to protect  personnel at increased special risk of exposure such as researchers and some healthcare workers.


Vaccinia is a distinct poxvirus, probably evolved from the smallpox or the cowpox virus, has been used for vaccination. Cowpox are more common in cats (catpox).  Monkeypox are found in Zaire. They all may produce similar symptoms like smallpox.

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